Stereotactic Body Radiotherapy for Lung Lesions using Multiple Phase 3D-CT Based on the Analysis of Radiobiological Parameters

Document Type : Original Paper


1 Department Of Radiation Oncology, Jaypee Hospital, Sector-128, Noida-201304, U.P. India

2 Amity Centre for Radiation Biology, Amity University, Noida-201304, U.P. India


Introduction: Planning target volume (PTV) is generated from internal treatment volume (ITV) using four-dimensional computed tomography (4D-CT) for enhanced therapeutic gain in the stereotactic body radiotherapy for lung lesions (SBRT-Lung). This study aimed to propose a strategy to generate ITV on multiple-phase 3D-CT and enhance therapeutic gain in SBRT-Lung.
Material and Methods: This study was conducted on 6 peripherally located and 5 centrally located lung lesions suitable for SBRT. The PTV was delineated based on 3D-CT datasets acquired at three different phases of respiratory motion. The prescribed dose of 50 Gy in 5 fractions was delivered using RapidArc technique. The therapeutic-gain was compared based on tumor control probability (TCP) and normal tissue complication probability (NTCP) against a multicenter trial, which uses single-phase 3D-CT for PTV delineation. The TCP and NTCP were calculated by Poisson’s linear-quadratic and Lyman-Kutcher-Burman models, respectively.
Results: Regarding the multicentre trial, the PTVs were maximally reduced to 42% and 57% among the 6 peripherally and 5 centrally located lung lesions, respectively. In peripheral lung lesions, TCP was significantly enhanced to 0.6% for long-term (>5years) local control (p <0.05), and NTCP was significantly reduced in pneumonitis (Grade≥II) of lung (0.2%; p <0.05). In central lung lesions, TCP was insignificantly enhanced; however, NTCPs were maximally reduced for cartilage necrosis in trachea (35%) and myelitis in spinal cord (19%).
Conclusion: The proposed strategy reduced the complications for normal tissues and enhanced therapeutic gain. The successful clinical outcomes validated our hypothesis in short-term (6-12 months), and we are currently testing the long-term efficacy.


Main Subjects

  1. References


    1. Xia T, Li H, Sun Q, Wang Y, Fan N, Yu Y, et al. Promising clinical outcome of stereotactic body radiation therapy for patients with inoperable Stage I/II non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2006 Sep 1;66(1):117-25.
    2. Baumann P, Nyman J, Hoyer M, Wennberg B, Gagliardi G, Lax I, et al. Outcome in a prospective phase II trial of medically inoperable stage I non small-cell lung cancer patients treated with stereotactic body radiotherapy. J Clin Oncol. 2009 Jul 10;27(20):3290-6.
    3. Timmerman R, Paulus R, Galvin J, Michalski J, Straube W, Bradley J, et al. Stereotactic body radiation therapy for inoperable early stage lung cancer. JAMA. 2010 Mar 17;303(11):1070-6.
    4. Chang JY, Senan S, Paul MA, Mehran RJ, Louie AV, Balter P, et al. Stereotactic ablative radiotherapy versus lobectomy for operable stage I non-small-cell lung cancer: a pooled analysis of two randomised trials. Lancet Oncol. 2015 Jun;16(6):630-7.
    5. Soldà F, Lodge M, Ashley S, Whitington A, Goldstraw P, Brada M. Stereotactic radiotherapy (SABR) for the treatment of primary non-small cell lung cancer; systematic review and comparison with a surgical cohort. Radiother Oncol. 2013 Oct;109(1):1-7.
    6. Zheng X, Schipper M, Kidwell K, Lin J, Reddy R, Ren Y, et al. Survival outcome after stereotactic body radiation therapy and surgery for stage I non-small cell lung cancer: a meta-analysis. Int J Radiat Oncol Biol Phys. 2014 Nov 1;90(3):603-11.
    7. Zhang B, Zhu F, Ma X, Tian Y, Cao D, Luo S, et al. Matched-pair comparisons of stereotactic body radiotherapy (SBRT) versus surgery for the treatment of early stage non-small cell lung cancer: a systematic review and meta-analysis. Radiother Oncol. 2014 Aug;112(2):250-5.
    8. ICRU Report 62. International Commission on Radiation Units and Measurements. Prescribing, Recording, and Reporting Photon Beam Therapy, Supplement to ICRU Report No. 50. Bethesda, MD: ICRU;1999.
    9. Shimizu S, Shirato H, Ogura S, Akita-Dosaka H, Kitamura K, Nishioka T, et al. Detection of lung tumor movement in real-time tumor-tracking radiotherapy. Int J Radiat Oncol Biol Phys. 2001 Oct 1;51(2):304-10.
    10. Chen QS, Weinhous MS, Deibel FC, Ciezki JP, Macklis RM. Fluoroscopic study of tumor motion due to breathing: Facilitating precise radiation therapy for lung cancer patients. Med Phys. 2001 Sep;28(9):1850-6.
    11. Sixel KE, Ruschin M, Tirona R, Cheung PC. Digital fluoroscopy to quantify lung tumor motion: Potential for patient-specific planning target volumes. Int J Radiat Oncol Biol Phys. 2003 Nov 1;57(3):717-23.
    12. Yu ZH, Lin SH, Balter P, Zhang L, Dong L. A comparison of tumor motion characteristics between early stage and locally advanced stage lung cancers. Radiother Oncol. 2012 Jul;104(1):33-8.
    13. Plathow C, Ley S, Fink C, Puderbach M, Hosch W, Schmähl A, et al. Analysis of intrathoracic tumor mobility during whole breathing cycle by dynamic MRI. Int J Radiat Oncol Biol Phys. 2004 Jul 15;59(4):952-9.
    14. Erridge SC, Seppenwoolde Y, Muller SH, van Herk M, De Jaeger K, Belderbos JS, et al. Portal imaging to assess set‑up errors, tumor motion and tumor shrinkage during conformal radiotherapy of non‑small cell lung cancer. Radiother Oncol. 2003 Jan;66(1):75-85.
    15. Videtic GM, Hu C, Singh AK, Chang JY, Parker W, Olivier KR, et al. A Randomized Phase 2 Study Comparing 2 Stereotactic Body Radiation Therapy Schedules for Medically Inoperable Patients with Stage I Peripheral Non-Small Cell Lung Cancer: NRG Oncology RTOG 0915 (NCCTG N0927). Int J Radiat Oncol Biol Phys. 2015 Nov 15;93(4):757-64.
    16. Wang L, Hayes S, Paskalev K, Jin L, Buyyounouski MK, Ma CC, et al. Dosimetric comparison of stereotactic body radiotherapy using 4D CT and multiphase CT images for treatment planning of lung cancer: evaluation of the impact on daily dose coverage. Radiother Oncol. 2009 Jun;91(3):314-24.
    17. Underberg RW, Lagerwaard FJ, Cuijpers JP, Slotman BJ, van Sörnsen de Koste JR, Senan S. 4-dimensional CT scans for treatment planning in stereotactic radiotherapy for Stage I lung cancer. Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1283-90.
    18. Lagerwaard FJ, Van Sornsen de Koste JR, Nijssen‑Visser MR, Schuchhard‑Schipper RH, Oei SS, Munne A, et al. Multiple “slow” CT scans for incorporating lung tumor mobility in radiotherapy planning. Int J Radiat Oncol Biol Phys. 2001 Nov 15;51(4):932-7.
    19. Wurstbauer K, Deutschmann H, Kopp P, Sedlmayer F. Radiotherapy planning for lung cancer: Slow CTs allow the drawing of tighter margins. Radiother Oncol.2005 May;75(2):165-70.
    20. Shih HA, Jiang SB, Aljarrah KM, Doppke KP, Choi NC. Internal target volume determined with expansion margins beyond composite gross tumor volume in three‑dimensional conformal radiotherapy for lung cancer. Int J Radiat Oncol Biol Phys. 2004 Oct 1;60(2):613-22.
    21. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
    22. Ohri N, Werner-Wasik M, Grills IS, Belderbos J, Hope A, Yan D, et al. Modeling local control after hypofractionated stereotactic body radiation therapy for stage I non-small cell lung cancer: a report from the elekta collaborative lung research group. Int J Radiat Oncol Biol Phys. 2012 Nov 1;84(3):379-84.
    23. Gay HA, NiemierkoA. A free program for calculating EUD-based NTCP and TCP in external beam radiotherapy. Phys Med. 2007 Dec;23(3-4):115-25.
    24. Martel MK, Ten Haken RK, Hazuka MB, Kessler ML, Strawderman M, Turrisi AT, et al. Estimation of tumor control probability model parameters from 3-D dose distributions of non-small cell lung cancer patients. Lung Cancer. 1999 Apr;24(1):31-7.
    25. Fenwick JD, Nahum AE, Malik ZI, Eswar CV, Hatton MQ, Laurence VM, et al. Escalation and intensification of radiotherapy for stage III non-small cell lung cancer: opportunities for treatment improvement. Clin Oncol (R CollRadiol). 2009 May;21(4):343-60.
    26. Webb S, Nahum AE. A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density. Phys Med Biol. 1993 Jun;38(6):653-66.
    27. Huang BT, Lu JY, Lin PX, Chen JZ, Li DR, Chen CZ. Radiobiological modeling analysis of the optimal fraction scheme in patients with peripheral non-small cell lung cancer undergoing stereotactic body radiotherapy. Sci Rep. 2015 Dec 11;5:18010
    28. Kim MS, Kim W, Park IH, Kim HJ, Lee E, Jung JH, et al. Radiobiological mechanisms of stereotactic body radiation therapy and stereotactic radiation surgery. Radiat Oncol J. 2015 Dec; 33(4): 265–75.
    29. Ruggieri R, Stavrev P, Naccarato S, Stavreva N, Alongi F, Nahum AE. Optimal dose and fraction number in SBRT of lung tumours: A radiobiological analysis. Phys Med. 2017 Dec;44:188-95.
    30. Brenner DJ.The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. SeminRadiat Oncol. 2008 Oct;18(4):234-9.
    31. Lovelock DM, Zatcky J, Goodman K, Yamada Y. The Effectiveness of a Pneumatic Compression Belt in Reducing Respiratory Motion of Abdominal Tumors in Patients Undergoing Stereotactic Body Radiotherapy. Technol Cancer Res Treat. 2014 Jun;13(3):259-67.
    32. Chairmadurai A, Goel HC, Jain SK, Kumar P. Radiobiological analysis of stereotactic body radiation therapy for an evidence-based planning target volume of the lung using multiphase CT images obtained with a pneumatic abdominal compression apparatus: a case study. Radiol Phys Technol. 2017 Dec;10(4):525-34.
    33. Purdie TG, Bissonnette JP, Franks K, Bezjak A, Payne D, Sie F, et al. Cone-beam computed tomography for on-line image guidance of lung stereotactic radiotherapy: localization, verification, and intrafraction tumor position. Int J Radiat Oncol Biol Phys. 2007 May 1;68(1):243-52.
    34. Bissonnette JP, Franks KN, Purdie TG, Moseley DJ, Sonke JJ, Jaffray DA, et al. Quantifying interfraction and intrafraction tumor motion in lung stereotactic body radiotherapy using respiration-correlated cone beam computed tomography. Int J Radiat Oncol Biol Phys. 2009 Nov 1;75(3):688-95.
    35. Guckenberger M, Wulf J, Mueller G, Krieger T, Baier K, Gabor M, et al. Dose-response relationship for image-guided stereotactic body radiotherapy of pulmonary tumors: relevance of 4D dose calculation. Int J Radiat Oncol Biol Phys. 2009 May 1;74(1):47-54.
    36. Muller-Runkel R, Vijayakumar S. Equivalent total doses for different fractionation schemes, based on the linear quadratic model. Radiology. 1991 May;179(2):573-7.
    37. AgrenCronqvist AK, Källman P, Turesson I, Brahme A. Volume and heterogeneity dependence of the dose-response relationship for head and neck tumours. Acta Oncol. 1995;34(6):851-60.
    38. Seppenwoolde Y, Lebesque JV, de Jaeger K, Belderbos JS, Boersma LJ, Schilstra C, et al. Comparing different NTCP models that predict the incidence of radiation pneumonitis. Normal tissue complication probability. Int J Radiat Oncol Biol Phys. 2003 Mar 1;55(3):724-35.
    39. Chapet O, Kong FM, Lee JS, Hayman JA, Ten Haken RK. Normal tissue complication probability modeling for acute esophagitis in patients treated with conformal radiation therapy for non-small cell lung cancer. Radiother Oncol. 2005 Nov;77(2):176-81.
    40. Senan S, Haasbeek NJ, Smit EF, Lagerwaard FJ. Stereotactic radiotherapy for centrally located early-stage lung tumors. J Clin Oncol. 2007 Feb 1;25(4):464.
    41. Onimaru R, Shirato H, Shimizu S, Kitamura K, Xu B, Fukumoto S, et al. Tolerance of organs at risk in small-volume, hypofractionated, image-guided radiotherapy for primary and metastatic lung cancers. Int J Radiat Oncol Biol Phys. 2003 May 1;56(1):126-35
    42. Hurkmans CW, Cuijpers JP, Lagerwaard FJ, Widder J, van der Heide UA, Schuring D, et al. Recommendations for implementing stereotactic radiotherapy in peripheral stage IA non-small cell lung cancer: report from the Quality Assurance Working Party of the randomised phase III ROSEL study. Radiat Oncol. 2009 Jan 12;4:1.
    43. Lagerwaard FJ, Haasbeek CJ, Smit EF, Slotman BJ, Senan S. Outcomes of risk-adapted fractionated stereotactic radiotherapy for stage I non-small-cell lung cancer. Int J Radiat Oncol Biol Phys. 2008 Mar 1;70(3):685-92.
    44. Haasbeek CJ, Senan S, Smit EF, Paul MA, Slotman BJ, Lagerwaard FJ. Critical review of nonsurgical treatment options for stage I non-small cell lung cancer. Oncologist. 2008;13:309-19.
    45. Timmerman R, McGarry R, Yiannoutsos C, Papiez L, Tudor K, DeLuca J, et al. Excessive toxicity when treating central tumors in a phase II study of stereotactic body radiation therapy for medically inoperable early-stage lung cancer. J Clin Oncol. 2006 Oct 20;24(30):4833-9.
    46. Lagerwaard FJ, van der Geld Y, Slotman BJ, Senan S. Quality of life after stereotactic radiotherapy for medically inoperable stage I non-small cell lung cancer. Int J Radiat Oncol Biol Phys.2006 Nov 1;66(1): S133-S4.
    47. Fowler JF, Tomé WA, Fenwick JD, Mehta MP. A challenge to traditional radiation oncology. Int J Radiat Oncol Biol Phys. 2004 Nov 15;60(4):1241-56.
    48. Onishi H, Araki T, Shirato H, Nagata Y, Hiraoka M, Gomi K, et al. Stereotactic hypofractionated high-dose irradiation for stage I non-small cell lung carcinoma: Clinical outcomes in 245 subjects in a Japanese multi institutional study. Cancer. 2004 Oct 1;101(7):1623-31.
    49. Wulf J, Baier K, Mueller G, Flentje MP. Dose-response in stereotactic irradiation of lung tumors. Radiother Oncol. 2005 Oct;77(1):83-7.
    50. Yoganathan SA, Maria Das KJ, Agarwal A, Kumar S. Magnitude, Impact, and Management of Respiration-induced Target Motion in Radiotherapy Treatment: A Comprehensive Review. J Med Phys. 2017 Jul-Sep;42(3):101-15.
    51. Li X, Yang Y, Li T, Fallon K, Heron DE, Huq MS. Dosimetric effect of respiratory motion on volumetric-modulated arc therapy-based lung SBRT treatment delivered by trueBeam machine with flattening filter-free beam. J Appl Clin Med Phys. 2013 Nov 4;14(6):4370.
    52. Ong C, Verbakel WF, Cuijpers JP, Slotman BJ, Senan S. Dosimetric impact of interplay effect on rapidArc lung stereotactic treatment delivery. Int J Radiat Oncol Biol Phys. 2011 Jan 1;79(1):305-11.
    53. Stambaugh C, Nelms BE, Dilling T, Stevens C, Latifi K, Zhang G, et al. Experimentally studied dynamic dose interplay does not meaningfully affect target dose in VMAT SBRT lung treatments. Med Phys. 2013 Sep;40(9):091710.
    54. Rao M, Wu J, Cao D, Wong T, Mehta V, Shepard D, et al. Dosimetric impact of breathing motion in lung stereotactic body radiotherapy treatment using intensity modulated radiotherapy and volumetric modulated arc therapy [corrected]. Int J Radiat Oncol Biol Phys. 2012 Jun 1;83(2):e251-6.
    55. Schuring D, Hurkmans CW. Developing and evaluating stereotactic lung RT trials: what we should know about the influence of inhomogeneity corrections on dose. Radiat Oncol. 2008 Jul 28;3:21.